Applicability of Arsenic minerals is known in traditional Chinese and Indian medicine since ancient times. In the 18th Century Thomas Fowler compounded a potassium bicarbonate based solution of arsenic trioxide (As2O3) which came to be known as Fowler's solution. Pharmacology texts of the 18th Century indicate the use of arsenical pastes for the treatment of variety of diseases including cancer [Karen H. Antman; Introduction: The history of arsenic trioxide in cancer therapy; The Oncologist 2001; 6(suppl 2):1-2]. In the 1990's it was reported by the Chinese investigators that herbal mixture containing arsenic trioxide could induce complete remission in patients suffering from acute promyelocytic leukaemia. [Dan Douer, Wendy Hu et. Al.; Arsenic trioxide (Trisenox) Therapy for Acute Promyelocytic Leukaemia in the setting of hematopoietic stem cell transplantation; The Oncologist 2003; 8:132-140].
Arsenic widely exists in nature in its trivalent and pentavalent forms. Arsenic toxicity highly depends on its chemical form. In Indian and Chinese traditional medicines three forms of arsenic minerals i.e., Orpiment, Realgar and Arsenolite, are used alone and also in conjunction with other minerals for treatment of various diseases. The disposition of these arsenicals in the body depends on various key factors, including solubility, absorption, distribution, and excretion. Arsenic trioxide is the most bio available but it is highly toxic compared to Orpiment and Realger. Realgar is also a major component in bhasmas of Indian Ayurvedic medicine. Realger is used both for external as well as internal application. Arsenic trioxide, obtained after purification of Arsenolite, has short term toxicity due to which its therapeutic application is a major concern. To increase the therapeutic application of Realgar, nano particles of Realgar is prepared by cryogrinding with polyvinylpyrrolidone and Sodium Dodecyl Sulphate. (Jie Liu et. al., Mineral Arsenicals in Traditional Medicines:Orpiment, Realger, and Arsenolite, The Journal of Pharmacology and experimental therapeutics, Vol. 326, No. 2, pg. 363-368, 2008).
Prior art search indicates that arsenic trioxide is and has been used in the treatment of cancer. EP2374463, EP2394702, EP 1562616, WO9924029, U.S. Pat. No. 6,884,439, U.S. Pat. No. 6,855,339, U.S. Pat. No. 6,982,096, U.S. Pat. No. 6,723,351, U.S. Pat. No. 6,720,011 are the results of prior art search indicating use of arsenic trioxide in therapy. However the present invention is unique in terms of the process of preparation and the novel nano arsenic trioxide obtained through the present inventive process is generally of particle size ranging from 10 nm to 1000 nm. Further, the novel product is chemically more stable, bio available and safe due to less toxic nature for therapeutic administration in humans, animals and plants. The prior art process for production of arsenic trioxide that is used for therapeutic application involves purification of arsenic trioxide through chemical process. The present invention purifies arsenic trioxide through bio synthesis.
The present invention relates to the production of novel nano arsenic trioxide by a novel process, which involves purification, making it chemically more stable, and particle size reduction of arsenic trioxide, with plant materials, buttermilk and goat urine. The plant materials used in the present process are Dolichos biflorous, Momordica charantia, Zingiber officinale, Musa paradisica. The scope of the invention also include use of the active ingredients found in the herein mentioned plant materials, buttermilk, goat urine or other plant, organic or inorganic materials, containing cellulose, with similar characteristics and chemical properties, as known to the people skilled in the art, for the purpose of inventive process and production of the novel product.
Buttermilk is a fermented dairy product obtained from cow's milk. The tartness of buttermilk is due to the presence of lactic acid. The pH level of buttermilk is generally noted to be 4.41 to 4.84. Butter milk can be made through traditional process, by culturing and also through acidification process of milk. One phase of the invention involves purification of arsenic trioxide with the aid of buttermilk. Use of buttermilk is one embodiment of this invention and it is possible to derive the same results if buttermilk is substituted with any other fermented form of milk either obtained through traditional methods or cultured. The substitution of fermented milk obtained through traditional methods or cultured with that of chemically produced or induced active ingredients with same effect known to people skilled in the art cannot be ruled out.
Goat and Cow urine have been an ingredient in Indian Ayurvedic medicine and other traditional Indian Medicine. Goat Urine is used in treatment of tuberculosis by tribals in Western ghats, India [P. Padmanabhan & amp; K. A. Sujana, 2008, Animal products in traditional medicine from Attapady hills of Western Ghats, Indian Journal of Traditional Medicine, Vol. 7(2), pg. 326-329]. However, the use of the goat urine as in the present process is not traditional knowledge or anticipated.
The medicinal values of plant materials belonging to genus Zingiber and family Zingiberaceae is well known in traditional medicines. Zingiber Officinale is plant species of genus Zingiber. The rhizome of Zingiber Officinale, Ginger, is one of the most widely used species of ginger family Zingiberaceae and is known for its medicinal use in traditional Chinese and Indian medicine. Ginger has many active ingredients such as Sesquiterpene hydrocarbons predominantly Zingiberene, active gingerols that can be converted to shogaols, Zingerone, Paradol. 6-Gingerol and 6-shogaols have shown pharmacological activities including anti pyretic, analgesic and in treatment of chemotherapy induced nausea (Monograph, Alternative Medicine Review, Volume 8, No. 3, 2003, pg. 331-335). However, use of ginger or extract of plant material of family of Zingiber Officinale for particle size reduction of metalloid is not known. The present inventive process also involve particle size reduction of arsenic trioxide to nano particles with aid of ginger.
Momordica charantia (Bitter Melon) is a tropical vegetable of family Cucurbitaceae. It is a flowering vine with known medicinal properties. Its fruits contain glycosides, saponins, alkaloids, reducing sugars, resins, phenolic constituents, fixed oils and free acids. Chemical constituents in Momordica Charantia are Alkaloids, charantin, charine, cryptoxanthin, cucurbitins, cucurbitacins, cucurbitanes, cycloartenols, diosgenin, elaeostearic acids, erythrodiol, galacturonic acids, gentisic acid, goyaglycosides, goyasaponins, guanylate cyclise inhibitors, gypsogenin, hydroxytryptamines, karounidiols, lanosterol, lauric acid, linoleic acid, linolenic acid, momorcharasides, momorcharins, momordenol, momordicilin, momordicins, momordicinin, momordicosides, momordin, momordolo, multiflorenol, myristic acid, nerolidol, oleanolic acid, oleic acid, oxalic, acid, pentadecans, peptides, petroselinic acid, polypeptides, proteins, ribosome-inactivating proteins, rosmarinic acid, rubixanthin, spinasterol, steroidal glycosides, stigmasta-diols, stigmasterol, taraxerol, trehalose, trypsin inhibitors, uracil, vacine, v-insulin, verbascoside, vicine, zeatin, zeatin riboside, zeaxanthin, zeinoxanthin Amino acids-aspartic acid, serine, glutamic acid, thscinne, alanine, g-amino butyric acid and pipecolic acid, ascorbigen, b-sitosterol-d-glucoside, citrulline, elasterol, flavochrome, lutein, lycopene, pipecolic acid.
Musa paradisica is a herbaceous plant of the genus Musa. The older scientific name Musa paradisica is seldom used due to the advent of hybrid varieties. Presently the species are referred to as Musa acuminata or Musa balbisiana or triploid hybrids. The fruit as well as the plant materials have medicinal value. In the present invention the extract of the plant material is used.
Dolichos biflorous is commonly used as an astringent, diuretic and tonic. The enzymes found in Dolichos biflorous have been identified as Urease, Allantoinase, Ribonuclease, Nicotinamide deaminase, b-n-acetylglucosaminidase, a and b galactosidase, a-mannosidase and b glucosidase.